Abstract 11723: Defects in the Branch-Chain Amino Acid Pathway is Associated With Doxorubicin-Induced Cardiotoxicity and Preventable With a BCKDK Inhibitor or Metformin

Abstract

Background: High exposure to doxorubicin (DOX) chemotherapy is associated with an 18-49% incidence of heart failure in cancer patients. However, the mechanism of cardiotoxicity remains elusive. Emerging evidence suggests that branched-chain amino acid (BCAA) catabolic defect is also a major metabolic hallmark in diseased hearts. However, to our knowledge, the role of cardiac BCAA in developing cardiotoxicity following chemotherapy is unknown. Hypothesis: We posit that dysfunction of branch chain amino acid catabolic flux is associated with doxorubicin-induced cardiotoxicity, and pharmacologic restoration of BCAA catabolic flux will restore cardiomyocyte function. Results: We generated a rat model of doxorubicin-induced heart failure. Using targeted metabolomic profiling, we observed branch chain amino acids (BCAA) are highly correlated with elevated levels of BNP and low ejection fraction. We have utilized human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to study the mechanism of DOX-induced toxicity. Our findings suggest that DOX significantly decreases mitochondrial activity. Specifically, we observed reduced activity of the mitochondrial enzyme BCKDH, a key regulator of BCAA flux. BCAA catabolism is restored following metformin treatment. Furthermore, we observe the inhibition of BCKDK with the allosteric inhibitor, BT2 (3,6-dichlorobenzo[b]thiophene-2 carboxylic acid), or metformin rescues cell toxicity. Conclusion: We have provided compelling evidence for targeting the BCAA pathway as a strategy for preventing cardiotoxicity. Further work is required to evaluate transcriptional changes driving DOX-mediated toxicity.